Death by dogma

I picked up this gem of a paper from, of all places, a blog with somewhat limited enthusiasm for ketogenic eating. I'll just go through the results section of the paper, giving a staccato summary of each paragraph, because you have to be sure of exactly what a group have found before you consider whether you agree with their conclusions. These mice lack the ability to form prelamin A correctly, instead they form progerin, and they age very rapidly. Here we go with the results section:

A mutation which damages nuclear architecture and causes premature aging also increases autophagy.

The abnormal protein formed (that prelamin A precursor known as progerin) appears to be the cause of premature aging and to be associated with increased autophagy (in this model).

Other models, XPF and CSB/XPA, of rapidly aging mice (both with defective DNA repair processes) do the same thing but without accumulating progerin, especially they increase basal autophagy. So this upregulated autophagy is common to several models of premature ageing, not just the prelamin A model.

mTOR signalling is switched off. Really switched off.

The PI3K-Akt pathway, which usually activates mTOR, is not the explanation.

AMPK is switched on. Really switched on.

Stopping the response to DNA damage (p53 knockout) does not stop enhanced AMKP activity. So we are not looking at extra autophagy to recycle damaged DNA.

Next we get on to glucose. The five hour starved level of glucose is low, around 38% of control value. Insulin is low too.

In the liver things are strange.

Phosphoenolpyruvate carboxykinase and glucose-6-phosphatase are up-regulated, both are important for gluconeogenesis.

Puryvate kinase (a glycolysis regulator) is not up-regulated. So where is the glucose going if it's not going to glycolysis?

Glucose from gluconeogenesis appears to end up in the liver as glycogen granules, without needing glycogen synthase to be up regulated. This glycogen can be accessed if needed.

At the same time fatty acid producing genes are up regulated. Glucose is being converted to fatty acids. Genes associated with fatty acid oxidation are up regulated too. And a fatty liver develops. Very interesting.

Pyruvate dehydrogenase kinase-4, key for switching from glucose to fat burning, is strikingly upregulated. These mice burn fat. They reject glucose. And they die of precocious aging!

All of the "good" markers indicating longevity in many models are fantastic in these mice. The end product is early death.

Metabolically, everything appears to come down to PGC 1-alpha. It's production is very upregulated. This cofactor appears to responsible for the switch from glucose to fat based metabolism.

End of results summary.

This is where the paper stops.

On the basis of these findings a concern expressed in the discussion is that elevated PGC 1-alpha drives autophagy, which is initially adaptive but might become maladaptive when chronically activated. This is a potentially valid concern (there is an autophagy triggered form of cell death distinct from apoptosis and necrosis) but we have to bear in mind that there is zero data to support this specific concern provided in the paper. That's all of the results section summarised up above.

The authors are well aware that the reason for rapid aging is the genetic defect in nuclear architecture formation. This leads, indirectly, to genomic instability which immediately puts this model in to the same category as other premature aging models such as XPF and CSB/XPA, both of which have defects in DNA repair, also as mentioned above.

So why do the cells of these animals go in to a state of AMPK driven, mTOR inhibition dependent, persistent autophagy?

They do this because they have a severe ATP deficit. High levels of AMP per unit ATP drive AMPK.

"Oxidative phosphorylation involves the transfer of electrons through a succession of redox centres in respiratory chains, from an electron donor such as NADH, to a terminal acceptor such as oxygen. A slowing of electron transfer means that respiratory complexes become more highly reduced, which increases their reactivity with oxygen, corresponding to a rise in free-radical leak [25]. A slowing of electron transfer is the most likely outcome of any mismatch between mitochondrial and nuclear genomes. The reason relates to the mechanism of electron transfer. If the gap between adjacent redox centres in respiratory chains is increased by just 1 A, electron transfer by quantum tunnelling slows down by an order of magnitude [26] and free-radical leak should rise accordingly. Given that hydrogen bonds and Van der Waal’s forces act over distances in the range of 1–2 A, it is likely that any changes to optimal subunit interactions would disrupt the distance between redox centres by more than 1 A, slowing electron flow and increasing free-radical leak. Thus, a rise in free-radical leak is the predicted outcome of virtually any subunit mismatch, and indeed has been reported [27, 28]"

Question: How well might the electron transport chain function in the mitochondria of a cell which has a permanent defect in its ability to repair nuclear DNA damage?

I think these mice are "starving" with full stomachs because they cannot generate ATP. They have progressive un-repaired changes to the nuclear DNA coding for (amongst many things) electron transport chain components which means these proteins simply don't fit the proteins from mtDNA.

Soooooooo. Essentially all of the changes in these mice could be traced back to inadequate ATP generation, with the added bonus of excess ROS generation to further damage the "unrepairable" DNA.

The extended autophagy is a total red herring, sort of.

I picked this paper up as a FB link "liked" by Chris Highcock. The linked blogger is so impressed by the lethal effect of autophagy that he appears to consider that diet-induced autophagy is a "worthless dogma" and avoids it, not liking dogma. That's fine by me, we all have our quirks.

Unfortunately for this autophago-phobic concept, and possibly for the poor chap himself, it turns out that if you take a prelamin A mutant mouse and treat it with rapamycin you will actually promote even MORE autophagy. So, if autophagy is the cause of premature aging, things should get worse. Yes? The actual result is that:

"Here, we report the discovery of rapamycin as a novel inhibitor of progerin [defective prelamin A], which dramatically and selectively decreases protein levels through a mechanism involving autophagic degradation. Rapamycin treatment of progeria cells lowers progerin, as well as wild-type prelamin A levels, and rescues the chromatin phenotype of cultured fibroblasts..."

As an approach, it works. Further increasing autophagy rescues prelamin A mutant mouse cells. RIP autophagy as a "cause" of accelerated aging.

I like Chris a lot, he's a really nice chap. Luckily the sort of hill walking he does (still love your Pentland pictures on FB, if you read this Chris) he will be regularly and repeatedly activating AMPK with subsequently increased autophagy. Exercise does this. So does the "misery" of ketogenic eating.

Actively changing your diet to avoid autophagy, based on a progerin model which can actually be rescued by increasing autophagy, just might be a booboo. Imitate with caution.

Peter

BTW It's sort of nice looking at technical papers which (superficially) challenge my low carbohydrate biased perspective. Knowing you are in a correct paradigm makes dissecting them a rather relaxed process when you start form a position where the world makes sense. Perhaps this is dogma.

21 comments:

"a proteolytic pathway that generates ATP and favors transition from prenatal to postnatal environment could also serve to adaptively retard aging and improve organismal homeostasis when triggered in adult tissues. Nevertheless, it is clear that this adaptive response is unable to repair or at least to compensate for the profound nuclear architecture defects derived from prelamin A accumulation in Zmpste242/2 mice, and these persistent defects lead to the premature death of these mutant mice."

It seems strange that the authors of the study recognize the up-regulation of autophagy mechanisms in these mice as a likely survival response, but then brush their own considerations aside by concluding (a bit simplistically) that since the observed mechanism occurs while these mice age prematurely…then…the process, sorta, kinda, must be….bad…right?

More shark attacks happen whilst ice-cream sales increase…Are the shark attacks caused from increased ice-cream consumption or because when it's warmer, people tend to swim in the ocean more and also eat more ice-cream? hhmmm...

QED says those who eat ice cream have less free electrons due to the lack of ATP and the sharks electric organs see the lack of energy in the prey and take it out because it perceives it is weak.......;)

Could they have the arrow of causation backwards? Shark attacks could cause people to eat more ice-cream.

I am absolutely amazed at the number of papers published where the authors don't seem to remember that correlation does not show causation. Even more seem to ignore that the arrow of causation could point either way - and even more don't seem to see why some folks bother to run replicable controlled studies.

In most of this work, it appears that a very few are pushing the science forward and far too many are simply muddying the water with poorly designed experiments (multiple variables changed (mice chow from two companies etc)) endless meta studies or just plain bogus data ( http://retractionwatch.com )

I don't *totally* understand this criticism here. It seems to be pointing at the mitochondria being compromised being the issue, and not getting enough ATP. And that is "blamed" on the type of rat they used in the study (which is probably true.) At the same time, a high fat, low carb diet is most likely going to damage your mitochondria and lead to reduced ATP as well. That's been pretty well documented from what I've seen.

Could someone kindly elaborate on Nick Lane’s point that “more free radicals are generated at rest, especially on a high-fat diet.” So, what is the alternative to HF diet then? See the full text below (from PSS) . Thanks.

“The balance between heat generation and ATP production still affects our health in surprising ways. Uncoupling of the respiratory chain is restricted in the tropics, because too much internal heat production would be detrimental in a hot climate: we could very easily overheat and die. However, this means that the ‘overflow channels’ are partially sealed off, so more free radicals are generated at rest, especially on a high-fat diet. This makes Africans eating a fatty western diet more vulnerable to conditions such as heart disease and diabetes, which are linked with free-radical damage. Conversely, the Inuit, who have a low incidence of such diseases, dissipate the proton gradient to generate extra internal heat in the frozen north. Accordingly, they have a relatively low free-radical leakage at rest and are less vulnerable to degenerative diseases.”

The thermal effect seems very dubious to me when thinking about tropical vs circumpolar. RMR may be higher on fat but post prandial thermogenesis is higher on carbs/protein. It seems as broad as it's long and I would rather have the modestly increased superoxide associated with normoglycaemic beta oxidation to maximise mitochondrial biogenesis...

This Nick Lane guy has never eaten real African food or else he wouldn't talk such rubbish as This makes Africans eating a fatty western diet because it is fatter than the SAD, at least in equatorial Africa. African diet uses lot of tubers and starches like maize and rice. But it is always accompagned with fatty cuts of meat and extremely fat gravies. They use liberally red palm oil, ghee and oil. So, implying the African diet to be fatter than western is ludicrous.Of course in parts of the continent that are dirt poor, people can not afford to put as much fat as they'd like, but even on Comoros where I've been for a certain time, they tried hard to get ghee, coconut, beef and mutton tallow. They eat even fatty fish no westerner would consider edible like gombessa (coelacanth).

About Me

I am Petro Dobromylskyj, always known as Peter. I'm a vet, trained at the RVC, London University. I was fortunate enough to intercalate a BSc degree in physiology in to my veterinary degree. I was even more fortunate to study under Patrick Wall at UCH, who set me on course to become a veterinary anaesthetist, mostly working on acute pain control. That led to the Certificate then Diploma in Veterinary Anaesthesia and enough publications to allow me to enter the European College of Veterinary Anaesthesia and Analgesia as a de facto founding member. Anaesthesia teaches you a lot. Basic science is combined with the occasional need to act rapidly. Wrong decisions can reward you with catastrophe in seconds. Thinking is mandatory.
I stumbled on to nutrition completely by accident. Once you have been taught to think, it's hard to stop. I think about lots of things. These are some of them.

Organisation (or lack of it)!

The "labels" function on this blog has been used to function as an index and I've tended to group similar subjects together by using labels starting with identical text. If they're numbered within a similar label, start with (1). The archive is predominantly to show the posts I've put up in the last month, if people want to keep track of recent goings on. I might change it to the previous week if I ever get to time to put up enough posts in a week to justify it. That seems to be the best I can do within the limits of this blogging software!